At the age of 11 (1527), Anne was betrothed to Francis, son and heir of the Duke of Lorraine while he was only 10.[7] Thus the betrothal was considered unofficial and was cancelled in 1535. Her brother William was a Lutheran but the family was unaligned religiously, with her mother, the Duchess Maria, described as a "strict Catholic".[8] The Duke's ongoing dispute over Gelderland with Emperor Charles V made them suitable allies for England's King Henry VIII in the wake of the Truce of Nice. The match with Anne was urged on the King by his chief minister, Thomas Cromwell.

Negotiations with Cleves were in full swing by March 1539. Cromwell oversaw the talks, and a marriage treaty was signed on 4 October of that year.

Henry valued education and cultural sophistication in women, but Anne lacked these: She had received no formal education but was skilled in needlework and liked playing card games. She could read and write, but only in German.[10] Nevertheless, Anne was considered gentle, virtuous, and docile, qualities that recommended her as a suitable candidate for Henry.

Anne was described by the French ambassador, Charles de Marillac, as tall and slim, "of middling beauty, and of very assured and resolute countenance".[11] She was fair haired and was said to have had a lovely face. In the words of the chronicler Edward Hall, "Her hair hanging down, which was fair, yellow and long ... she was apparelled after the English fashion, with a French hood, which so set forth her beauty and good visage, that every creature rejoiced to behold her".[12] She appeared rather solemn by English standards, and looked old for her age. Holbein painted her with high forehead, heavy-lidded eyes and a pointed chin.

Henry met her privately on New Year's Day 1540 at Rochester on her journey from Dover.[13] Henry and some of his courtiers, following a courtly-love tradition, went disguised into the room where Anne was staying, and Henry boldly kissed her.[13] According to the testimony of his companions, he was disappointed with Anne, feeling she was not as described. According to the chronicler Charles Wriothesley Anne "regarded him little",[14] though it is unknown if she knew if this was the king or not.[15] Henry did then reveal his true identity to Anne, although he is said to have been put off the marriage from then on. Henry and Anne then met officially on 3 January on Blackheath outside the gates of Greenwich Park, where a grand reception was laid out.[16]

Most historians believe that he later used Anne's alleged 'bad' appearance and failure to inspire him to consummate the marriage as excuses, saying how he felt he had been misled, for everyone had praised Anne's attractions: "She is nothing so fair as she hath been reported," he complained.[17] Henry urged Cromwell to find a legal way to avoid the marriage but, by this point, doing so was impossible without endangering the vital alliance with the Germans.

Despite Henry's very vocal misgivings, the two were married on 6 January 1540 at the royal Palace of Placentia in Greenwich, London by ArchbishopThomas Cranmer. The phrase "God send me well to keep" was engraved around Anne’s wedding ring. Immediately after arriving in England, Anne conformed to the Anglican form of worship, which Henry expected.[19] The couple's first night as husband and wife was not a successful one. Henry confided to Cromwell that he had not consummated the marriage, saying, "I liked her before not well, but now I like her much worse." He described her as having unpleasant body odour and sagging breasts, among other complaints.[20] In February 1540, Anne praised the King as a kind husband to the Countess of Rutland, saying: "When he comes to bed he kisseth me, and he taketh me by the hand, and biddeth me 'Good night, sweetheart'; and in the morning kisseth me and biddeth 'Farewell, darling.'" Lady Rutland responded: "Madam, there must be more than this, or it will be long ere we have a duke of York, which all this realm most desireth."[21]

Anne was commanded to leave the Court on 24 June, and on 6 July she was informed of her husband's decision to reconsider the marriage. Witness statements were taken from a number of courtiers and two physicians which register the king's disappointment at her appearance. Henry had also commented to Thomas Heneage and Anthony Denny that he could not believe she was a virgin.[22] Shortly afterwards, Anne was asked for her consent to an annulment, to which she agreed. The marriage was annulled on 9 July 1540, on the grounds of non-consummation and her pre-contract to Francis of Lorraine. Henry VIII's physician stated that after the wedding night, Henry said he was not impotent because he experienced "duas pollutiones nocturnas in somno" (two nocturnal pollutions while in sleep; i.e., two wet dreams).[23][24]

The former queen received a generous settlement, including Richmond Palace, and Hever Castle, home of Henry's former in-laws, the Boleyns. Anne of Cleves House, in Lewes, Sussex, is just one of many properties she owned; she never lived there. Henry and Anne became good friends—she was an honorary member of the King's family and was referred to as "the King's Beloved Sister". She was invited to court often and, out of gratitude for her not contesting the annulment, Henry decreed that she would be given precedence over all women in England save his own wife and daughters.[2]

After Catherine Howard was beheaded, Anne and her brother, the Duke of Cleves, pressed the king to remarry Anne. Henry quickly refused to do so.[25] She seems to have disliked Catherine Parr, and reportedly reacted to the news of Henry's sixth marriage with the remark "Madam Parr is taking a great burden on herself."[26]

On 4 August 1553, Anne wrote to Mary to congratulate her on her marriage to Philip of Spain.[29] On 28 September 1553, when Mary left St James's Palace for Whitehall, she was accompanied by her sister Elizabeth and Anne of Cleves.[30] Anne also took part in Mary I's coronation procession,[31][32] and may have been present at her coronation at Westminster Abbey.[33] These were her last public appearances. As the new Queen was a strict Catholic, Anne yet again changed religion, now becoming a Roman Catholic.[34][35]

After a brief return to prominence, she lost royal favour in 1554, following Wyatt's rebellion. According to Simon Renard, the imperial ambassador, Anne's close association with Elizabeth had convinced the Queen that "the Lady [Anne] of Cleves was of the plot and intrigued with the Duke of Cleves to obtain help for Elizabeth: matters in which the king of France was the prime mover".[36] There is no evidence that Anne was invited back to court after 1554.[37] She was compelled to live a quiet and obscure life on her estates.[37] After her arrival as the King's bride, Anne never left England. Despite occasional feelings of homesickness, Anne was generally content in England and was described by Holinshed as "a ladie of right commendable regards, courteous, gentle, a good housekeeper and verie bountifull to hir seruants."[4]

When Anne's health began to fail, Mary allowed her to live at Chelsea Old Manor, where Henry's last wife, Catherine Parr, had lived after her remarriage.[38] Here, in the middle of July 1557, Anne dictated her last will. In it, she mentions her brother, sister, and sister-in-law, as well as the future Queen Elizabeth, the Duchess of Suffolk, and the Countess of Arundel.[39] She left some money to her servants and asked Mary and Elizabeth to employ them in their households.[40] She was remembered by everyone who served her as a particularly generous and easy-going mistress.[4]

Anne died at Chelsea Old Manor on 16 July 1557, eight weeks before her forty-second birthday. The cause of her death was most likely to have been cancer.[38] She was buried in Westminster Abbey, on 3 August,[41] in what has been described as a "somewhat hard to find tomb" on the opposite side of Edward the Confessor's shrine and slightly above eye level for a person of average height. She is the only wife of Henry VIII to be buried in the Abbey.

She also has the distinction of being the last of Henry VIII's wives to die[4] (she outlived Henry's last wife, Catherine Parr, by 9 years). She was not the longest-lived, however, since Catherine of Aragon was 50 at the time of her death.[40]

Anne is the subject of three biographies: Julia Hamilton's Anne of Cleves (1972), and Mary Saaler's Anne of Cleves: Fourth Wife of Henry VIII (1995), and Elizabeth Norton's Anne of Cleves: Henry VIII's Discarded Bride (2009). Retha Warnicke has written an academic study on Anne's marriage called The Marrying of Anne of Cleves. Royal Protocol in Early Modern England (2000).

Anne of Cleves appears as a character in many historical novels about Henry's reign. In The Fifth Queen (1906) by Ford Madox Ford she is portrayed as a sensible, practical woman who happily settles for annulment in return for material benefits. Anne of Cleves is the main character of My Lady of Cleves (1946) by Margaret Campbell Barnes. About a third of The Boleyn Inheritance (2006) by Philippa Gregory is recounted from Anne's point of view, covering the period of Henry VIII's marriages to her and to her successor Catherine Howard. The book concludes with Anne living away from court, and avoiding the execution ceremonies of Howard and of Jane Boleyn, sister-in-law to one of Henry's queens and lady-in-waiting to all the others, including Anne. Gregory includes Anne in a non-fictional review of the period at the end of the book.

Anne and her Holbein portrait in the Louvre are the focus of the novel Amenable Women (2009) by Mavis Cheek.[42] Anne and Catherine Howard are the subject of The Queen's Mistake by Diane Haeger (2009), while Anne and Jane Seymour are covered in Volume 3 of Dixie Atkins's tetralogy A Golden Sorrow (2010).

The role of Anne of Cleves was played by Elsa Lanchester in The Private Life of Henry VIII, which was released in 1933. Lanchester's husband Charles Laughton played Henry VIII and won an Academy Award for his portrayal. The film received a Best Picture nomination; the first for a picture made outside the U.S.

Anne of Cleves was played by Elvi Hale in the episode Anne of Cleves in the television series The Six Wives of Henry VIII. This series portrays Anne as a personally naive yet politically clever woman who convinces Henry against consummating the union so that he can get out of his alliance with the Germans should the need arise. When Anne's predictions prove true, it is she who suggests becoming "the King's beloved sister".

The role of Anne of Cleves was played by actress and singer Joss Stone in the Showtime cable television series The Tudors. The series downplays Anne's naiveté and exaggerates her popularity so as to provide a foil for the immature, unpopular Katherine Howard. The series also has an anachronistically svelte Henry engaging in an affair with Anne after his marriage to Catherine, realizing too late that he "like[s] her after all."

In The Simpsons episode "Father Knows Worst", when Homer falls asleep while building a balsa wood model of Westminster Abbey, he has a vision of the ghost of Anne of Cleves played by Pamela Hayden. In the episode "Margical History Tour," Anne is portrayed by Otto Mann during Marge's retelling of Henry's reign. Henry (portrayed by Homer) quickly orders Anne's beheading after realizing she is a he.